RENAL DATA FROM ASIA–AFRICA
|Year : 2020 | Volume
| Issue : 5 | Page : 1078-1084
|Clinicopathologic Features and the Association with Short-Term Outcome of Primary Membranous Nephropathy in Children: A Single-Center Study from Pakistan
Madiha Aziz1, Afshan Ehsan1, Muhammed Mubarak2, Ali Asghar Lanewala1, Seema Hashmi1
1 Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
2 Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
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|Date of Web Publication||21-Nov-2020|
| Abstract|| |
Membranous nephropathy (MN) is an uncommon cause of steroid-resistant nephrotic syndrome in children. Our study aimed to determine the clinicopathologic features of primary MN in children and their association with short-term outcome. This observational study was conducted from January 2009 to June 2017 at the Pediatric Nephrology Department. A total of 50 children were diagnosed with primary MN. Their clinical, laboratory, and histopathological findings on renal biopsy were recorded. The minimum follow-up was for six months. Clinicopathologic features were correlated with the outcome at the last follow-up. Data analysis was done using IBM SPSS Statistics for Windows software version 20.0. The mean age at onset was 10.92 ± 3.08 years (range: 4–17 years). The male-to-female ratio was 3:1. The serum albumin of ≤2.5 g/dL was seen in 40 patients (80%), hypertension was present in 38 (76%), and heavy proteinuria was seen in 32 children (70%). The mean estimated glomerular filtration rate (eGFR) at presentation was 178.71 ± 0.78 mL/min/1.73 m2. At the initial visit, nine children (18.4%) were in chronic kidney disease stage 2 and one (2%) in stage 4. Phospholipase A2 receptor antibody was present in five (15%) of 32 children tested. At the last follow-up (28 interquartile range: 25.5 months), 11 children (26%) were in complete remission and 25 (66%) had achieved partial remission. The mean eGFR had reduced to 145.84 ± 78.05 mL/min/1.73 m2. Patients with normal initial eGFR were more likely to go into remission (P = 0.001). The short-term outcome of childhood primary MN is relatively good in our setup. A multicenter collaborative study is required to determine prognostic factors and to standardize treatment in this uncommon nephropathy.
|How to cite this article:|
Aziz M, Ehsan A, Mubarak M, Lanewala AA, Hashmi S. Clinicopathologic Features and the Association with Short-Term Outcome of Primary Membranous Nephropathy in Children: A Single-Center Study from Pakistan. Saudi J Kidney Dis Transpl 2020;31:1078-84
|How to cite this URL:|
Aziz M, Ehsan A, Mubarak M, Lanewala AA, Hashmi S. Clinicopathologic Features and the Association with Short-Term Outcome of Primary Membranous Nephropathy in Children: A Single-Center Study from Pakistan. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 2];31:1078-84. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1078/301174
| Introduction|| |
Membranous nephropathy (MN) is an uncommon cause of childhood nephrotic syndrome (NS). It may present with sub-nephrotic range proteinuria to overt NS in the setting of steroid-resistant NS (SRNS). In children, it is often secondary to infections, autoimmune diseases, drugs, and malignancies. Once those causes are excluded, the incidence of primary MN has been reported to vary from 1.5% to 9.1% in different studies. Mubarak et al in 2009 reported a prevalence of MN in 7.96% of all renal biopsies performed for idiopathic NS in children in their study.
Since all children with subnephrotic and asymptomatic proteinuria do not seek physician care and are much less biopsied, the overall prevalence of MN in children may be much higher than appreciated.
The clinical course of MN is variable, and patients may undergo spontaneous remission without treatment, complete or partial remission with therapy, or progress to end-stage renal disease despite treatment. Subnephrotic range proteinuria with normal renal functions can be treated conservatively with angiotensin blockade. Those with NS are usually treated with steroids initially, followed by alkylating agents or calcineurin inhibitors, if there is no remission with angiotensin blockade. However, the relapse rate after their discontinuation remains high. The practitioner treating MN in the pediatric patient must weigh the risks of immunosuppressive therapy against the benefits.
Due to the low prevalence of MN as well as slow rate of progression, the study of clinical features and optimal treatment options of MN in children is still evolving. The conclusions of treatment regimens given for new-onset disease are conflicting and elusive. Similarly, attempts to prognosticate factors such as extent of proteinuria at outset, hypertension, serum creatinine and albumin, age at onset, and histopathological features have also remained inconclusive in children.
This study aimed to determine the clinicpathologic features, treatment, and short-term outcome of MN for the first time in a pediatric population of Pakistani origin. It also aimed to determine if any of the clinical, laboratory, or histological features at presentation correlates with the development of renal insufficiency or affect remission of proteinuria.
| Subjects and Methods|| |
This observational analysis included all children who underwent renal biopsy for SRNS from January 2010 to June 2017 at the Pediatric Nephrology Department, Sindh Institute of Urology and Transplantation, and were diagnosed with MN. A total of 1469 renal biopsies were performed in children during this 7.5-year period, out of which 579 biopsies were performed for SRNS. During this period, of the children who were biopsied, 58 had primary MN, but no clinical records for eight children could be traced, and hence, the study was conducted on 50 patients. Each patient's record was reviewed at presentation and at the last visit with a minimum follow-up period of at least six months. Patients with systemic lupus erythematosus (SLE), hepatitis B and C, and other secondary causes of MN were excluded.
Demographic, clinical, laboratory, histopathological findings and treatment were recorded from the files. Patient data were collected using a predesigned pro forma. Laboratory investigations including serum creatinine, serum albumin, urinary dipstick for proteinuria, and hematuria were noted. Serological tests conducted for antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) (where applicable), and hepatitis B, C, complement levels (C3 and C4) and phospholipase A2 receptor (PLA2R) antibody were also recorded, if available.
The histopathological details obtained from biopsy reports were presence or absence of tubular atrophy, interstitial fibrosis, and deposition or absence of immunoglobulins IgG, IgM, IgA, C3, and C1q on immunofluorescence.
Treatment options included angiotensin blockade [angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB)], calcineurin inhibitors: cyclosporine and tacrolimus, and calcium channel blocker, amlodipine. All patients were given a full dose of steroids 2 mg/kg/day for at least four weeks before being labeled SRNS and then biopsied.
Laboratory data at the final visit determined classification of patients into either complete, partial, or no remission. Renal insufficiency, if present, was categorized according to the stages of chronic kidney disease (CKD).
Heavy proteinuria was defined as 3+ to 5+ on urine dipstick testing. Hematuria was present if urine dipstick read 1+ or more. Estimated glomerular filtration rate (eGFR) was calculated using the age and gender appropriate modified Schwartz formula. Patients with an eGFR less than 90 mL/min/1.73 m2 were considered to have renal insufficiency and classified according to the stage of CKD as per the KDOQI guidelines. Hypertension was identified using the National High Blood Pressure Education Program Working Group 2004 guidelines, based on gender, age, and height percentiles. Complete remission (CR) was defined as absence of edema, negative proteinuria on dipstick, and serum albumin more than or equal to 2.5 g/dL. Partial remission (PR) was defined as serum albumin more than 2 g/dL and absence of edema with proteinuria less than 3 g/day (urine dipstick 1+ to 3+). Patients with serum albumin <2 g/dL, persistent edema, and presence of proteinuria (urine dipstick 1+ to 5+) were considered to have (no remission) NR.
| Statistical Analysis|| |
Data were entered and analyzed using IBM SPSS Statistics for Windows software version 20.0 (IBM Corp., Armonk, NY, USA). Data are presented as mean ± standard deviation and median with interquartile range for continuous variables and as numbers and percentages for categorical variables. Pearson-Chi-square test was applied to determine the association between clinicopathologic factors including eGFR at onset and the outcome. Results were considered statistically significant if the P <0.05.
| Results|| |
Of the 50 patients with primary MN, the results were analyzed for 45 patients who completed the study. The mean age at presentation was 10.92 ± 3.1 years (range: 4–17), and about one-third of patients were younger than 10 years [Table 1]. At the first evaluation, 33 (66%) had microscopic hematuria and 10 (20.4%) had an eGFR <90 mL/min/1.73 m2, with 9 (18.4%) of them being in CKD stage 2 and 1 (2%) in stage 4. Low serum albumin of ≤2.5 g/dL was seen in 40 patients (80%) at initial visit. ANA was weakly positive in nine patients (18%), but none had presence of anti-double-stranded DNA (dsDNA) or the characteristic clinical or histopathological features of SLE. Complement levels C3 and C4 were normal in all patients, and their biopsies lacked full-house immunofluorescence, especially the presence of C1q positivity. PLA2R antibody was positive in five patients (15%) and borderline in two (6%) from among the 32 children tested.
Idiopathic MN was seen in all the renal biopsies done. Results showed that IgG deposition was predominant in 47 (94%) and interstitial fibrosis was seen in two children (4%).
Calcineurin inhibitors were prescribed in nine patients (18%). Two of them were lost to follow-up. Cyclosporine was given to seven patients. Of these seven, one was on maintenance dose of 2 mg/kg/day and five of them had shown a decline in renal function, and hence, cyclosporine was stopped and they were kept on ACEIs and ARBs. Out of the five children with renal insufficiency, one expired, one had CR and one achieved PR, and both of them also showed complete recovery of renal functions. Two patients had further deterioration of renal function and progressed to CKD stage 5. Acute tubular necrosis developed in one patient due to acute gastroenteritis. She later recovered and went into spontaneous CR [Figure 1].
|Figure 1: Outcome of patients given cyclosporine A.|
CyA: Cyclosporine A, ATN: Acute tubular necrosis, CR: Complete remission, PR: Partial remission, CKD: Chronic kidney disease, ACEI: Angiotensin-converting enzyme inhibitors, ARB: Angiotensin receptor blockers, f/up: Follow-up, Maint: Maintenance dose.
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Thirty children (66%) remained in remission with stable renal functions out of which 11 (37%) were in CR while 19 (63%) were in PR. The mean serum creatinine rose from 0.53 ± 0.04 mg/dL to 1.13 ± 1.86 mg/dL and mean serum albumin increased from 1.78 ± 0.78 g/dL to 3.08 ± 1.06 g/dL. Heavy proteinuria (3+ to 5+ on dipstick) persisted in 24 patients (48%) in comparison to 38 (76%) at initial visit.
Out of those 24 patients (48%) who continued to have heavy proteinuria, 20 had a serum albumin of >2 g/dL with no edema (PR) and only four had persistent edema with serum albumin less than 2 g/dL (NR). The mean eGFR reduced from 179 ± 74 mL/min/1.73 m2 at the onset to 146 ± 78 mL/min/1.73 m2 at the end of the study.
There were 15 children (33%) who had an eGFR<90 mL/min/1.73 m2. This subgroup was compared with the group that maintained normal renal functions. Among all the known variables that may predict renal failure, a normal GFR at the time of presentation stood as a significant factor for better outcome (P = 0.001). None of the other initial clinical or laboratory features, such as hypertension, heavy proteinuria, hematuria, serum albumin, presence of PLA2R antibody or biopsy findings of IgA deposition, tubular atrophy, interstitial fibrosis, and glomerular sclerosis, had any prognostic effect on the outcome in terms of remission or progression to renal failure [Table 2].
|Table 2: Clinical, laboratory, and pathological factors affecting outcomes.|
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| Discussion|| |
This descriptive, observational single-center analysis showed favorable outcome in children with primary MN who had normal renal function at onset, since they were more likely to go into remission. None of the other studied prognostic factors were found to have statistical significance probably due to the small sample size.
Primary MN in Pakistani children who undergo renal biopsy for idiopathic SRNS has been reported to be 7.96%–14.7%, which is 5–10 times higher than what has been reported in studies from Europe and North America. The International Study of Kidney Disease in Children reported an incidence of 1.5% in children biopsied for idiopathic NS. MN made up 8.2% of the histological lesions seen in children who were biopsied for SRNS at our institute but accounted for only 4.4% of biopsies for the same in an Indian study by Gulati et al. This marked variability could perhaps be explained by differences in ethnicity, genetic factors, and biopsy indications. Although rare in children, MN has been seen in children as young as 2 years., The age at onset in our study ranged from 4–17 years,, with the average age of onset being 9–11 years. No gender predilection was reported by Menon et al and Valentini et al, Lee et al, and Chen et al. Our study had a preponderance of males as also reported by Latham et al.
Better prognostic indicators like age at onset <10 years as seen in the cohort reported by Olbing et al and Trainin et al were not seen in our population. Similarly, poor prognostic indicators such as hypertension and heavy proteinuria at onset as reported by Latham et al, Ramirez et al, Trainin et al, and Habib et al also did not achieve statistical significance in our population.
Contrary to what has been reported in the literature in studies of adults,, biopsy findings of glomerular sclerosis and tubulointerstitial change did not affect the outcome in this study nor in the cohort studied by Valentini et al. Further, Lee et al and Chen et al also did not report any significant difference in prognosis.
M-type PLA2R is the implicated causative antigen in majority of the cases of primary MN in adults. Antibodies against this receptor have been detected in 70–75% of adults with primary MN. In contrast, the sensitivity of this antibody falls to 45% in children, as also seen by Cossey et al PLA2R antibodies were seen in only five (15%) out of 32 patients tested in our study population. Neutral endopeptidase and cationic bovine serum albumin are the other two antigens that have been implicated in early primary childhood membranous nephropathy but are currently not being investigated at our institute., It is entirely possible that there are other etiologic agents in our children which have not been discovered yet.
CR of proteinuria was seen in 33% of patients in the series by Olbing et al and 29% in the follow-up by Latham et al which are comparable to our results of 37% CR but lower than the rate (52%) observed by Habib et al and CR (75%) as reported by Valentini et al This can perhaps be explained by the fact that cases of asymptomatic or non-nephrotic range proteinuria that are more likely to go into CR are not routinely biopsied at our institute. Elsewhere, Lee et al have reported a higher overall remission rate of 75% which is close to our total remission of 66%.
The natural history of MN follows the rule of thirds with one-third spontaneous remission, one-third persistent proteinuria, and one-third of patients progressing to renal failure. Children tend to have better renal outcomes than adults, and chronic renal insufficiency rates of 17.6% and 25% have been reported by Lee et al and Chen et al. This study showed a similar result of 33% patients ending in renal insufficiency, out of whom 7% were nearing dialysis.
Conflict of interest: None declared.
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Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi
[Table 1], [Table 2]
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